Project Summary/Abstract Degeneration of select neuronal populations is a pathological hallmark of both, Alzheimer?s (AD) and Parkinson?s disease (PD), but the mechanisms accounting for selective vulnerability or resistance are only poorly understood. Loss of midbrain dopamine (DA) neurons in the substantia nigra (SNc) precipitates the defining symptoms in PD, while it is the decline of neurons in the forebrain that drive core AD symptoms. Importantly, there is considerable overlap in the neurodegeneration of subcortical nuclei, with age as the most critical risk factor, suggesting that AD and PD share common pathogenic mechanisms. One common feature of these vulnerable populations that has not yet been appreciated is that they each transiently express VGLUT2 during development, but later repress it in the adult. Further, we determined that, in at least some of these vulnerable populations, VGLUT2 expression can re-emerge with insult. Re- emergence of VGLUT2 could initially be a beneficial compensatory adaptation, for example by increasing vesicular neurotransmission or promoting synaptogenesis. However, we found that sustained VGLUT2 expression induced severe neurodegeneration of SNc DA neurons suggesting that the timing and balance of VGLUT2 expression are crucial determinants of neuronal survival. I propose that re-emerging VGLUT2 is a hallmark of prodromal neurodegeneration in vulnerable populations of PD and AD. During my K99 phase, I will determine the molecular mechanism of how VGLUT2 overexpression induces neurodegeneration in susceptible populations by using a combination of genetic, molecular, physiological and histological techniques. I will train in slice electrophysiology and human neuropathology to complement my strong background in molecular biology, biochemistry and pharmacology. Through my co-mentors? expertise in neurodegenerative disorders, I will determine, if VGLUT2 is upregulated in vulnerable neuronal populations of human PD and AD using in situ hybridization, and determine whether VGLUT2 is a biomarker of ongoing neurodegeneration. During my R00 phase, I will test whether aging or neuronal injury induce re-emergence of VGLUT2 in vulnerable neuronal populations using AD mouse models, and elucidate whether VGLUT2 re-emergence causally contributes to their degeneration in my independent laboratory. Collectively, this work will reveal unappreciated contributions of VGLUT2 regulation to neurodegenerative processes in AD and PD and potentially provide new and sorely needed targets for therapeutic intervention.